Antibiotics

Penicillin
 Penicillin
• According of mode of action:
– Inhibition of cell wall synthesis:
• They includes:
• ß-lactams antibiotics
– Penicillins
– Cephalosporins
– Monobactams
– Carbapenems

– Mode of action:
– Inhibit the synthesis of peptidoglycan (murine layer); consequently, the cell wall is
greatly weakened and the cell undergoes lyses.
– It has very little toxicity for host cells, since human cells don't have peptidoglycan cell
walls.
 β-Lactam
– Include all of four-membered lactam ring
– Penicillin, cephalosporines, monolactams, carbapenems and β-
lactam inhibitors
– Penicillin have thiazolidine ring atttached to β-lactam ring (RNH)
– Nucleus 6-aminopenicillanic acid (6APA)
– Gram –ve, T.B, non-bacterial pathogen ---resistant
– Natural penicillin (benzyl penicillin, penicillin G):
• Narrow spectrum
• Easily inactivated (alkali, acid, heat, metals, OA, alcohol)
• Parentral
• Rapid excretion
– With probencid (slow excretion)
– Slowly adsorbed cpd (procaine, benzamide, benzathine)
– Acid resistant (penicillin V, phenoxmethyl penicillin)
• Emerging bacterial resistant (use)
 Mode of action of Penicillin
– Site of action:
– attacks bacterial cells by inactivating an enzyme that is essential for bacterial
growth. The enzyme is peptidoglycan transpeptidase (Penicillin Binding
Proteins, PBPs, which act as receptor for penicillin) and it catalyses the cross-
linking of the peptidoglycan, which forms the cell wall of the bacteria.
– The peptidoglycan transpeptidase enzyme is not needed in animals as their
cells do not have cell walls.
– A final bactericidal event is the removal or inactivation of an inhibitor of autolytic
enzymes in the cell wall. This activates the autolytic enzymes and results in cell
lysis.
– The penicillin stops the growth of the bacterial cell wall, causing the pressure
inside the cell to rise considerably until the cell lyses and thus the cell is
destroyed.
– Mechanism of action:
– binds at the active site of the transpeptidase enzyme that cross-links the
peptidoglycan strands. It does this by mimicking the D-alanyl-D-alanine
residues that would normally bind to this site
 β-lactams
1- Penicillins
Natural
 Resistance to Penicillin
– Resistance to penicillin falls into several categories:
1. Production of β-lactamases (catalyse the hydrolysis of β-lactams) by staphylococci,
gram negative bacteria, haemophilia, gonococci, and others.
2. Lack of PBPs or altered PBPs (eg, pneumococci, enterococci) or inaccessibility of
receptors because of permeability barriers of bacterial outer membranes.
3. Failure of activation of autolytic enzymes in cell wall, which can result in inhibition
without killing bacteria (eg,tolerance of some staphylococci).
4. Failure to synthesize peptidoglycans, such as in mycoplasmas, L forms, or
metabolically inactive bacteria.

– β-lactamases
– They hydrolysing the labile β-lactam ring bond, the penicillin can no longer react
with the transpeptidase enzyme. Thus the antibacterial properties of the
penicillin have been deactivated
– Penicillin are inactive against organisms devoid of a peptidoglycan cell wall,
such as mycoplasma, protozoa, fungi, and viruses.
 Penicillin members
• Members:
• Classical β-lactames:
• Penicillin
• Natural penicillin
• Produced by mould Penicillium nutatum and Penicillium
chrysogenum
• Acid resistant → taken orally (penicillin V)
• Acid labile → taken parentally (penicillin G).
• Disadvantage:
• 1- narrow spectrum
• Easily inactivated (heat, acid, alki…etc)
• Taken praentlelly
• Inactivated by b-lactamases
• Rapidly excreted in urine, blood level falls quickly, dose every 6
hours
 Penicillin members
• Semi-synthetic.
• Nucleus: 6-aminopenicillanic acid (6-APA) obtained either by penicillin
production in absence of precursor or by using penicillin amidases (acylases).
• Acylation of 6-APA with appropriate substances results in new penicillins
• The clinically important penicillins fall into four principal groups:
• 1- highest activity against gram-positive organisms, spirochetes, and some
others but susceptible to hydrolysis by β-lactamases and acid labile (eg,
penicillin G)
• 2- relative resistance to β-lactamases but lower activity against gram-positive
organisms and inactivity against gram-negative organisms (eg, nafcillin)
• 3- relatively high activity against both gram-positive and gram-negative
organisms but destroyed by β-lactamases (eg, ampicillin, piperacillin).
• 4- relative stability to gastric acid and suitable for oral administration (eg,
penicillin V, cloxacillin, amoxicillin).
• Procaine salts and benzathine salts of penicillin provide repository forms for
intramuscular injection.
 Semi-synthetic Penicillins
– Penicillin acylase remove side chain----nucleus 6APA
– Add side chain to 6APA
– Classification of penicillins:
• Standard (penicillin G)
– G +ve, g-ve cocci, non-bata lactamase anaerobes
– β- lactamase sensitive
• β- lactamase resistant
– Isoxazole penicillin (oxacillin, cloxacillin, dicloxacillin, flucloxacillin)
– Flucloxacillin is the antibiotic of chose for oral adminstration because of its
higher adsorption
– Penicillinase, acid resistant—oral
– Bulk group---hinders
» Naphthalin, ethoxy----nafcillin
» Heterocyclic ring----oxacillin
» Steric hindrance-----methicillin
– Antistaphylococcal penicillins (nafcillin, methicillin, isoxazole penicillin)
» Inactive against enterococci, anerobic bacteria and g-ve cooci and rods
 Semi-synthetic Penicillins
• Extended-spectrum penicillins:
– Ampicillin and amoxicillin
– Taken orally, active against enteric –ve bacteria, typhoid, dysentery bacilli and
haemophilus influenzas
– Amoxicillin is a drug of choice for upper respiratory tract infection
– Anti-pseudomonal penicillins
• Carbenicillin and its ester, ticarcillin, piperacillin, mezlocillin and azlocillin (substituted
ampicillin)
• Ccarbenicillin is especially used for UTI
• Destroy by β-lactamase
• Stable to acid (GIT)—oral
– Ampicillin, amoxicillin (better adsorption)
– + β-lactamase inhibitors---expand spectrum
» Amoxicillin+ clavulanic acid (Augmentin)
» Ticarcillin+ clavulic acid (Timentin)
» Ampicilin+ sulbactam (Unasyn)
» Tazobactam+ piperacillin (Tazocin)
 Semisynthetic
penicillin
Carbenicillin &
β- lactamase
resistant narrow piperacillin
spectrum: G +ve Azlocillin
(Staphylococci) β- lactamase
Methicillin sensitive
Spectrum as
(injection) Ampicillin & Ampicillin
Cloxacillin & Amoxacillin more G- negative
Flucloxacillin & Oral coverage
Broad spectrum - Used in urinary tract
nafacillin (β- infections
lactamase and acid β- lactamase
sensitive Active against P.
resistant, given
Amoxacillin has aeruginosa
orally)
better absorption
than ampicillin.
Used for upper
respiratory tract
infections
Piperacillin activity
against???
 Clinical uses of Penicillin
• Penicillin G is the drug of choice in most infections caused by streptococci,
susceptible pneumococci, meningococci, spirochetes, clostridia, aerobic
gram-positive rods, non– penicillinase-producing staphylococci, and
actinomycetes.
• Benzathine penicillin G: treatment for group A streptococcal pharyngitis
and primary syphilis. Prophylaxis against group A streptococcal in
rheumatic fever.
• Cloxacillin or dicloxacillin, staphylococcal infections
• Amoxicillin given together with clavulanic acid is active against β-
lactamase-producing H influenzae.
• piperacillin–tazobactam combination β-lactamase–producing gram-
negative rods
• Piperacillin is more effective against aerobic gram-negative rods,
especially pseudomonads.
• Side effects:
• Hypersenstivity
 β-Lactams inhibitors
– β-Lactams inhibitors:
– β-lactamase inhibitors are given in combination with penicillin to tackle the
problem of the resistance caused by β-lactamases from bacterial cells
– Example: Augmentin
– which is a combination of amoxicillin [a semi-synthetic penicillin, R =
CH(NH2)(C6H6OH)] and clavulanic acid [a β-lactamase inhibitor].
– Clavulanic acid inhibits the β-lactamase enzyme by binding to a serine
residue in the active site
– Unasyn
– Combinations of ampicillin and sulbactam (penicillanic acid sulphone
derivative) are marketed for the treatment of skin tissue, and gynecologic
infections.
– Tazocin, Zosyin
– Piperacillin and Tazobactam (penicillanic acid sulphone derivative)
– Timentin
– Ticarcillin and Clavulanate
β- lactam+ β- lactamase inhibitors
• Ampicillin + Sulbactam = Unasyn
• Amoxicillin + Clavulanic acid = Augmentin
• Piperacillin + Tazobactam = Tazosin
Monobactams &
Carabapenems
 Monobactams & Carabapenems
• Monobactam
• Single ring β-lactams
• Against G-ve, stable to most types of b-lactamases
• Aztreonam
– Used for Enterobacteriaceae. G-ve bacteria (meninges, kidney and bladder)
– Active against Pseudomonous aerogenia
• Clavams
• Replacement of sulphur in the penicillin thiazolidine ring with oxygen in the clavam oxazolidine ring
and the absence of the sidechain at position 6 Clavulanic acid
• Not antibacterial
• Powerful β-lactamase inhibitor
• + ampicillin, amoxycillin
• Carabapenems
• They are analogues of penicillins or clavams, the sulphur (penicillins) or oxygen (clavams) atom
being replaced by carbon. Examples are the olivanic acids and thienamycin and imipenem Broad
spectrum
• Thienamycins
• Ex Imipenem and merpenem, Ertapenem, Doripenem (IV adminstration due to poor oral
bioavailability)
– » Impenem → more active against G +ve than merpenem. (against many gram-negative rods,
gram-positive organisms, and anaerobes.)
– » Meropenem → more active against G –ve than impenem.
– Doripenem more active against P aeruginosa than imipenem but equal in activity to meropenem.
 Semisynthetic penicillin
β- lactamase resistant
Monobactams β- lactam + β- Carbapenems
Example: lactamase Example:
inhibitors Imipenem &
Aztreonam Meropenem
Narrow spectrum (G-
Broadest spectrum
ve) used for UTI
(various type of
Administered by
infections, reach all
injection IM or IV
tissues)
(G-ve, G+ve, P.
aeruginosa
Administered IV

20
Semi-synthetic Penicillins, Summary
– Acid resistant → oxacillin, cloxacillin, dicloxacillin & flucloxacillin.
– Acid labile → not given orally as they will be damage by HCl. E.g.
Methicillin (taken parentally)
– Acid resistant (taken orally):
– a) Ampicillin: reach the blood in low level with low penetration in
spinal fluid.
• Piperacillin (derivative of ampicillin, by piperazine ring)
• Increases the activity against G –ve bacteria and thus
decreasing that of G +ve.
–  b) Amoxicillin: reach blood in high level with high penetration in
spinal fluid.
Semi-synthetic Penicillins, Summary
– Acid labile (taken parentally): mainly active against G +ve bacteria
– a) Anti-pseudomonical penicillin: e.g. Carbencillin – ticaricillin.
• Highly active against (Pseudomonous, Proteus, Enterobacter).
• Inactive against (Klebicella).
• Less active against all G +ve bacteria and H. influenza. →
Temocillin: highly active against H.influenza but still inactive
against G +ve.
– b) Enterobacteriaceae: e.g. Mecillinam
• Active against rapidly growing fermented G –ve rods. (E. coli,
Proteus, Klebicella & Salmonella)
• Not used against Pseudomonous because Pseudomonous is
oxidative not fermentative microorganism.
• Not used against H. influenza because it is low growing
although it is G –ve and fermentative.
Cephalosporins
 β-lactams
Cephalosporins
2nd generation
Cefamandol
1st generation Cefoxitin 3rd generation
Cephaloridine B-lactamase resistant Ceftazidime
Cephalexin Active against G+ve Cefotaxime.
Active against cocci & many G-ve Active against Few
rods G+ve & most G-ve &
G+ve cocci & Hospital-acquired
Few G-ve rods (eg. Klebsiella & H. M.O
B-lactamase influenza) (Pseudomonas,
sensitive Serratia,
Enterobacter), used
for serious Infections
4th generation
 Cefipime
Most G+ve and G-ve & B- lactamase
Resistant
(Pseudomonas, Serratia, Enterobacter)
used in serious infections that resist 3rd
generation
 Cephalosporins
• Same mode of action
• Broader spectrum
• Nucleus 7-aminocephalosporanic acid (7ACA) produce in large
quantities ----semi-synthetic (cephamycins)
• Total synthetic-----moxalactam
• They are water soluble and pH stable
• Classified to four generation according to spectrum
– First generation:
• Cephadroxil, cefazolin, cephalexin, cephalothin, cephapirin and cephradine
• Like ampicillin (spectrum, pH stability)
• Resistance to β-lacatmase Staphylococcus aureus
• Cephaloridine---G+ve, nepherotoxic (aminoglycosides, diuretics)
• Cephradine and Cephalexin—oral
 Cephalosporins
– Second generation:
• Cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil and ceforanide
• Cephamycines (cefoxitin, cefmetazole, loracarbef and cefotetan)
• Spectrum include first generation + G-ve and some anaerobes
• mostly given by injection
– Third generation:
• Cefoperazone, moxalactam, cefotaxime, ceftazidime, ceftizoxime, ceftrioxone,
cefixime, cefpodoxime, proxetil and ceftibuten
• Spectrum: g+ve, g-ve and cross blood brain barriers
• 100 fold active the 1st and 2nd generation and active against Pseudomonas
– Fourth generation
• Fourth generation cephalosporins are extended spectrum agents with similar
activity against gram-positive organisms as first generation cephalosporins. They
also have a greater resistance to beta-lactamases than the third generation
cephalosporins. Many can cross blood brain barrier and are effective in meningitis.
• The fourth generation cephalosporins are Cefepime, Cefluprenam, Cefozopran,
Cefpirome, Cefquinome.
• Cefepime penetrated outer membrane of G-ve, than 3 rd generation, parentally
administer
28
Cephalosporins
Cephalosporins
 Cephalosporins, Summary
– a) First generation (narrow spectrum):
• Oral → Cephalexin and Cephadroxil.
• Parental → Cefazoline.
• Oral or parentral → Cephradine.
• Active against G+ve (Staphylococcus, Streptococcus pneumonia, Enterococcus).
• Less active against G –ve.
• Less active against anaerobic microorganism.
–  b) Second generation (expanded spectrum):
• Oral → Cefaclore.
• Parental → Cefoxitine, Cefotitan, Cefiroxine & Cefalomycin.
• Activity towards G –ve is increased so, used in the treatment of H. influenza, N. gonorrhea,
E. coli, Salmonella, Proteus, Shigella and Cetrobacter.
• Its effect on G +ve isn't lessened.
–  c) Third generation (Broad spectrum):
• Oral » cefixime.
• Parentral » ceftriaxone, ceftazidime, cefotaxime & cefoperazone.
• Become much more active against Pseudomonous aerogenia & G –ve bacteria →
Enterobacteriaceae, H. influenza & N. gonorrheae.
• Lower activity against G +ve (not used).
– d) Forth generation (Extended spectrum):
• Parentral » cefepime.
• More active against G –ve bacteria & Pseudomonous.
• Not used for G +ve.
Cephalosporins in the market

F 2nd
generation
1st
generation

3rd
generation

4th
generation
 Fusidic acid
– From fungus Fusidium coccineum
– Steroid structure
– Oral
– Against Staphylococcus aureus (as well β-lactamase producer)
– Have active uptake
– In combination with cloxacillin or flucloxacillin (emerge resistance)
 Macroloides
– Reacts with the 50S portion of Generic name Trade name
the 70S prokaryotic ribosome Azithromycin Zithromax
– Includes
Clarithromycin Biaxin, Biaxin XL
– Erythromycin
– Oleandomycin Dirithromycin Dynabac
– Spiramycin
Erythromycin Ery-Tab, Eryc,
– Clarithromycin
Ilosone, EryPed,
– azithromycin various
– Organism
Troleandomycin Tao
– Streptomyces erythreus
– Oral (as estolate, stearate)
– In pediatrics (low toxicity)
– Prophylaxis in whooping cough
– Drug of choice (campylobacter and legionella)
– erythromycin activity like Penicillin G, used in penicillin hypersensitivity, used for
pediatric due to lack of toxicity and available in oral acceptable oral suspension
or base
– Use in prophylactic drug in whooping cough
 Lincosamines
– Includes
– lincomycin
– Clindamycin
– bind selectively to a region of the 50S ribosomal subunit close to that of
chloramphenicol and erythromycin
– block elongation of the peptide chain by inhibition of peptidyl transferase
– Semi-synthetic of lincomycin
– Improve activity and absorption
– Structurally related to erythromycin
– Penetrate bone (osteomyelitis)
– Active against G+ve cocci, anaerobes and Strptococcus pyogenes
 Aminoglycosides
– Interfere with the initial steps of protein synthesis by changing the shape of 30S portion of the
70S prokaryotic ribosome. This cause the genetic code on the m-RNA to be read incorrectly.
– Most derived from Streptomyces species (mycin)
– Derived from Micromonospora (micin)
– Characteristics:
– Bactericidal, aerobic G-ve and Staphylococcus aureus
– Not active g+ve, anaerobes
– Taken parentally
– Nephrotoxic
– Neurotoxic (8 nerve) causing ototoxicity, usually irreversible defenses
– Cannot penetrate cerebrospinal fluid
– Members:
– Streptomycin, first drug line against T.B, ototoxic, in combination with Isoniazid &PAS
– Gentamycin, wide rang of bacteria, especially Pseudomonas in combination with
carbenicillin to delay resistance
– Kanamycin
– Tobramycin
– Amikacin
– Neomycin, Framycin (soframycin) very toxic oral, used topically cream , oint, eye drop
– Framycin specially used in burn
– Spectinomycin
 Aminoglycosides
– Streptomycin:
– T.B in combination (isoniazid)
– Ototoxicity
– Gentamycin:
– More active
– Against Pseudomonas aeruginosa
– Kanamycin:
– T.B
– Broad spectrum
– Less toxic
– Tobramycin:
– Derivative of kanamycin
– Amikacin:
– Semi-synthetic of kanamycin
– Neomycin and Framycin:
– Topical due to toxicity
– Spectinomycin:
– Aminocyclitol
– Treatment of gonorrhea (single IM dose)
 Rifamycins
– Rifampicin:
– Semisynthetic of Rifamycin (A, B, C, D and E)
– natural rifamycin rapidly excreted in bile low activity
– Rifampicin is Taken orally, good absorption, less excreted
– High blood level
– G+ve, some G-ve and T.B
– Taken in combination due
to development of resistance
– Penetrate cerebrospinal fluids
– Used in tuberculous meningitis
– Treatment of H. influenza and meningococci infection
– Adverse effect:
– Jaundice
– GIT disturbance
 Chloramphenicol
• Inhibition of protein synthesis:
– Inhibits the formation of peptide
bonds in the growing polypeptide chain
– Affect 50S RNA
– Streptomyces venzuelae
– Synthetic production
– Broad spectrum (bacteria, rikettisae, chlamydia and some viruses)
– Bacteriostatic
– Oral, penetrate cerebrospinal fluid
– Typhoid fever and meningitis
– More effective when taken orally
– Topical (ointment, drops….etc)
– Adverse effect:
• Fatal bone marrow depression
(aplastic anemia)
 Tetracyclines
• Inhibition of cell wall synthesis:
• binding to 30S subunit to block access of the amino acyl-tRNA to the mRNA-
ribosome complex at the acceptor site
• Four ringed structure, some naturally and some synthetic
• Broad spectrum, Bacteriostatic
• Spectrum gram-positive and gram-negative bacteria and rickettsiae, chlamydiae,
and Mycoplasma pneumoniae, cholera to shorten excretion of vibrios
• Members:
• Chlortetracycline
• Oxytetracycline
• Tetracycline
• Newer generation, well adsorbed, slowly excreted, single dose
– Doxycycline
– Minocycline, effective against resistance strains of Staphylococcus
• Adverse effect:
• Nousea, vomiting, diarrhea)
• Food (milk and milk product), aluminum hydroxide gels, calcium, iron and magnesium
salts impair absorption
• Less binding of calcium with doxycycline and minocycline
• Yellow staining of teeth specially children and pregnant women
• Liver damage and teratogenicity in pregnant women
• Minocycline effective against Staphylococcus
 Polymyxins
• Inhibition of cell membrane function:
• Changes the permeability of the plasma membrane
• Cationic detergent
• Binds to negatively charged phosphate groups of LPS
• Polypeptide antibiotic (Bacillus spp)
• Bactericidal
• Effectiveness:
• Pseudomonas aeruginosa, G-ve rods
• Not adsorbed, can be used fir intestine infection
• Orally for local treatment
• Topical
• All are nephrotoxic, however polymyxin B and E is less toxic, used as IM
injection in severe illness
• As powder and ointment for burn infection
 Chemotherapeutic agents
Sulfonamides
• Inhibitors of folic acid synthesis:
• Analogues to PABA
• Cheap
• Bacterostatic
• Harmless to patients
• Classified to four groups according to absorption
and excretion:
• Rapidly absorbed and excreted
• Rapidly absorbed and slowly excreted
• Non adsorbed
• Sulfonamides for special use
 Sulfonamides
• Rapidly absorbed and excreted:
• Members:
• Sulfadiazine
• Sulfaisoxazole
• Acute UTI
• Sulfaisoxazole (acid pH stable)
• Sulfadiazine (poor stability at acidic pH)
• When treat patient with UTI----alkali (Na2HCO3)
• To prevent crytalluria
• Sulfadiazine----penetrate cerebrospinal fluid---meningitis

• Rapidly absorbed and slowly excreted:

• Members:
• Sulfamethoxazole
• Combination with trimethoprin (co-trimoxazole)
• Typhoid fever, gonorrhea
 Sulfonamides
• Non absorbed Sulfonamides:
• Members:
• Succinyl and phthalyl sufathiazole (sulfasuccidine)
• Pre-operative suppression of bowel flora
• Bacillary dysentery

• Sulfonamides with special use:

• Sulfacetamide
• Penetrate well in in eye
• Eye drops, ointment
 Trimethoprim
• Block DHF to tetrahydrofoloic acid in bacteria
• Synergistic effect with sulfamethoxazole
• 1:5 mixture with sulfamethoxazole
• Co-trimoxazole
 Folate antagonists

Petridine PABA

Dihydropteroic
acid
DHF

THF
Folic acid

Important cofactor in the synthesis of adenine, guanine, thymine and

methionine (DNA nucleotides bases).
A combination of trimethoprim & sulfamethoxazole
gives a synergistic effect.
p-aminobenzoic acid + Pteridine
dihydropteroate
Sulfonamides synthetase

Dihydropteroic acid

Dihydrofolate
synthetase

Dihydrofolic acid
Dihydrofolate
Trimethoprim reductase

Tetrahydrofolic acid

Thymidine Methionine
Purines
 Quinolones
• Quinolones:
• Inhibit bacterial DNA gyrase
• Members:
• Early quinolones:
• Nalidixic caid, against G+ve, G-ve resistant, used for UTI
• Oxolinic acid
• Cinoxacin
• UTI
• Side effects: nausea, vomiting,
abdominal pain, urticaria, rash, photo sensitivity and fever, visual
disturbance, hallucination
• Fluorinated derivatives:, Enterobacteriaceae, Pseudomonas,
Staphylococcus but not streptococcus
• Norfloxacin (100 times active than Nalidixic acid) anti-
pseudomonal infection, UTI
• Ciprofloxacin
• Ofloxacin
• perfloxacin
• Pseudomonas and Staphylococcus
 Nitrofurans
• DNA strand break by direct chemical action
• Synthetic compounds
• Members:
– Nitrofurazone (topical, wound )
– Furazolidone (eneterocolitis)
– Nitrofurantion (UTI, oral, well absorbed, excreted rapidly)

• nitroimidazoles:
• Syhthetic compound have imidazole ring
– Metronidazole: antianaerobic
– By anaerobe reduced to compound make DNA breaks
• Clostridium, protozoa (Trichomonas vaginalis)
– Antigungal
– Clotrimazole, Econazole, Miconazole, ketoconazole
– Antifungal activity (yeast, dermatophytes, tinea)
 Antifungal agents
• Topical:
– Polyenes (candidiasis) not dermatophytes
• bind to ergosterol
• Amphotericin
• Nystatin
• Natamycin
– Imidaizoles: (tinea, candidiasis)
• inhibit synthesis of sterol of fungal
membrane
• Clotrimazole
• Miconazole
• Econazole
• Systemic:
– Amphotricin B (invasive yeast,
dimorphic fungi)
– Flucytosine (invasive candidiasis)
– Griesofulvin (tinea (scalp and nails)), accumulate in skin
– Ketoconazole (oral)
– Miconazole (IV) –Hestoplasmosis, invasive candidiasis
and dermatophytes
Antifungal agents
 Anti- tuberculosis drugs
• T.B intracellular organism
• Persistence, due to intracellular, waxy cell wall
• Three standard drugs:
– Streptomycin
– P-aminosalicylic acid (PAS)
– Isonicotinic acid hydrazide (INH)
• Now a day: Pyridoxine
• First line drugs: (oral) Isoniazid
– Rifampicin,
• Expensive, labile to cause hepatitis
– Isoniazid Mycolic acid
• Cheap, effective, develop resistance, cause hepatitis
• affects on the enzyme that converts pyridoxine
into mycolic acid (in T.B), thus stop its formation.
– Ethambutol
• Second line drugs (have side effects)
– Streptomycin (injection)
– Pyrazinamide (bactericidal, penetrate CNS used for tubercular meningitis)
– Thiacetazone (effective, side effect hepatitis, hemolytic anemia)
 Anti- tuberculosis drugs
• Management of T.B infection
– At least two drugs in combination
– Or three
• Rifampicin, isoniazid, ethambutol
– Duration
• Four drugs for two months
– Rifampicin, isoniazid, pyrazinamide
Streptomycin
• Followed by two drugs for 4-6 months
• Isoniazide and rifampicin
– Cough treatment

– X-ray, microbiological test for all contacts

 Antiviral agents
• Virus are obligate intracellular parasites
• Antiviral drugs
– Block entry
– Destroy virus inside the cell
• Virus replication
– Adsorption and penetration
– Un-coating
– Synthesis of early virus genes
– Synthesis of late virus genes
– Assembly
– Release
• Close resemble to host cell, use
• Cell machinery to synthesis protein
• And DNA
 Binding

Reverse transcription Fusion

Integration
Endocytosis
Transcription Nuclear localization

Splicing Uncoating
RNA export
Lysosome
Maturation
Genomic RNA Assembly
Modification
mRNA Budding
Translation
 Antiviral agents
• Anti-Herpes agents:
– Members:
• Acyclovir
• Ganciclovir
• Iduxuridine, inhibit viral DNA synthesis, use topically due to toxcity
• Cytarabine
• Vidarabine
– Acyclovir:
• Acyclic gaunosine derivatives
• Effective against
– Herpes simplex type 1 and 2 (HSV)
– Varicella-Zoster virus (VZV)
– Epstein-Barr virus (EBV)
– Cytomegalovirus
– Herpes virus type 6
• By virus thymidine kinase, convert to monophosphate derivative, to di and
triphosphate by cellular enzymes
• Inhibit virus DNA synthesis
– Competitive inhibition of dGTP for virus DNA polymerase
– Bind to DNA templet---chain termination
• Resistance may occur due to alteration of thymidine kinase or DNA polymerase
Anti-Viral Chemotherapy
Nucleic Acid Synthesis
Polymerases are often virally encoded

Other enzymes in nucleic acid synthesis

e.g. THYMIDINE KINASE in Herpes Simplex
 Anti-Viral Chemotherapy
Thymidine Kinase
Viral or cellular
thymidine kinase Deoxy-thymidine
adds first
phosphate
Deoxy-thymidine
triphosphate

Cellular kinases add PO4 PO4 PO4

two more
phosphates to form
TTP
 Anti-Viral Chemotherapy
Why does Herpes simplex code for its own
thymidine kinase?
TK- virus cannot grow in neural cells because they
are not proliferating (not making DNA)
Although purine/pyrimidines are present, levels of
phosphorylated nucleosides are low
Allows virus to grow in cells that are not making
DNA
 Anti-Viral Chemotherapy
Herpes thymidine kinase will phosphorylate any
deoxynucleoside including drugs – as a result of its
necessary non-specificity
Nucleoside analog may be given in non-phosphorylated form
• Gets drugs across membrane
• Allows selectivity as only infected cell has enzyme to
phosphorylate the drug
Cellular TK (where
expressed) does not
phosphorylate ACG P P P
(activate) the drug
 Anti-Viral Chemotherapy
Need for activation restricts drug to:
• Viruses such as HSV that code for own thymidine kinase
• Virus such as cytomegalovirus and Epstein-Barr virus that induce cells to overproduce
their own thymidine kinase

• In either case it is the VIRUS-INFECTED cell that activates the drug

 Anti-Viral Chemotherapy
Thymidine kinase activates drug but phosphorylated drug
inhibits the polymerase

Nucleotide analogs
Sugar modifications
Base modifications

Selectivity
• Viral thymidine kinase better activator
• Cellular enzyme may not be present in non-proliferating cells
• Activated drug is more active against viral DNA polymerase
that against cell polymerase
 Anti-Viral Chemotherapy
Guanine analogs
Acyclovir = acycloguanosine
= Zovirax
Ganciclovir = Cytovene
• Activated by viral TK
• Activated ACV is better
(10x) inhibitor of viral
DNA polymerase than
Acyclovir Ganciclovir inhibitor of cell DNA
polymerase, but is also
much more toxic; it is
reserved for the treatment
of severe CMV in
immunocompromised
Excellent anti-herpes drug patients.
 Anti-Viral Chemotherapy
Acyclovir: A P

• Chain terminator
P
Termination T
Selective:
• Virus phosphorylates P
drug G

• Polymerase more P
ACG C
sensitive
P-P-P
Also inhibits: P
A
• Epstein Barr
• Cytomegalovirus
 Anti-Viral Chemotherapy
Acyclovir very effective against:
• Herpes simplex keratitis (topical)
• Latent HSV (iv)
• Fever blisters – Herpes labialis (topical)
• Genital herpes (topical, oral, iv)
Resistant mutants in thymidine kinase or DNA
polymerase
Appears not to be teratogenic or carcinogenic
Ganciclovir very effective against cytomegalovirus – viral
DNA polymerase is very sensitive to drug activated by
cell TK
 Anti-Viral Chemotherapy
• Famciclovir is similar, being a pro-drug of
penciclovir (an antiviral with similar activity
to aciclovir)
• Valociclovir is a pro-drug ester of aciclovir.
 Anti-Viral Chemotherapy

Adenine arabinoside (Ara-A)

Problems : Severe side effects
• Resistant mutants (altered polymerase)
Competitive • Chromosome breaks (mutagenic)
inhibitor of • Tumorigenic in rats
virus DNA
polymerase • Teratogenic in rabbits
which is
• Insoluble
much more
sensitive Use: topical applications in ocular herpes simplex
than host
polymerase
 Antiretroviral agents
• Reverse transcriptase inhibitors
– Zidovudine (azidothymidine, AZT), use for AIDS treatment, inhibit DNA
replication
– Didanosine
– Zalcitabine
– Uses
• Anti-HIV
• Protease inhibitors
– Indinavir + reverse transcriptase inhibitors
– Uses:
• HIV-1 infection
 Anti-HCV
• Interferon / Ribavirin
• Direct-acting antivirals (DAAs) all are oral
– Protease inhibitor antiviral medications (NS3/4A inhibitors)
• paritaprevir (for genotype 1)
• simepravir (Olysio) (for genotypes 1 and 4)
• grazoprevir (for genotypes 1 and 4)
– Directed inhibitors (NS5A inhibitors)
• adispavir (a component in the combination drug Harvoni)
• ombitasvir (a component in the combination drug Viekira Pak)
• elbasavir (a component in the combination drug in Zepatier)
• daclatasvir (Daklinza)
– Polymerase inhibitors (NS5B Inhibitors) and combination drugs
• Sofosbuvir (Sovaldi)
• Ledipasvir/sofosbuvir (Harvoni)
• Viekira Pak dasabuvir, ombitasvir, paritaprevir, and ritonavir.
• Dasabuvir prevents the building blocks of the virus from coming together.
• Ombitasvir blocks the formation of a protein that helps the virus copy itself.
• Paritaprevir helps stop the building of small pieces that make up the virus.
• Ritonavir helps increase the effectiveness of paritaprevir by making it last longer in your body.
 Antiviral agents
• Other antiviral agents
– Amantadine and Rimantadine
• Inhibit uncoating of viral RNA of influenza A—prevent replication
 Anti-Viral Chemotherapy
Amantadine: 1966
Rimantadine: 1993
Only effective against ‘flu A (200mg/day)
• Marginally effective therapeutically
• Prophylaxis: Reduce flu by 90% Amantadine Rimantadine
Since disease usually mild and avoidable not used much
here
Good alternative to vaccine for: Lysosomotropic
• Elderly drugs?
Affects M2 protein involved in
• Immunocompromized activation of virus before
release from cell or uncoating
• Allergic
after entry
• Where causative strain not the vaccine
strain
 Interferon
• Group of endogenous proteins---non specific antiviral activities
• Low molecular weight protein produced by viral infected cells
• Classification:
• IFN-α (type I, leucocyte), produced by viral infected cells, induce virus resistant state
• IFN-β (type I, fibroblast)
• IFN-γ (typeII, immune), produced by lymphocytes prevent spread of virus from cell to cell
(used for tumor therapy)
– Elaborate effectors proteins in infected cells, inhibition of viral replication
– IFN-α use for hepatitis B and C, AIDS associated Kaposi´s sarcoma

• Ribavirin
– Guanosine analogue
– Phosphorated intracellular (guanosine triphosphate)
– Inhibit capping of viral mRNA
– Uses:
• Influenza A virus
• Para influenza
• Respiratory syncytial virus
• Paramyxoviruses
• HCV
• HIV-1
 Cancer
Immunotherapy
 Cancer Immunotherapy
• Beyond surgery and radiation treatment, Drug therapy for cancer
falls loosely into four categories:
– Chemotherapies, aimed at blocking DNA synthesis and cell
division
– Hormonal therapies, which interfere with tumor-cell growth
– Targeted therapies, such as small molecule inhibitors of
cancer
– Immunotherapies, which induce or enhance the antitumor
immune response.

• Eliminate a tumor by reviving, initiating, or

supplementing the in vivo anti-tumor immune response
or by neutralizing inhibitory pathways.
Monoclonal Antibodies can be targeted to tumor cells
• At present, approximately 12 different mAbs are licensed for the
treatment of cancer.
• May be used unmodifi ed or can be conjugated with an agent to
increase their efficacy.
• For instance, toxins, chemical agents, and radioactive particles can
be attached to a mAb, which then delivers the conjugated
substance to the target cell.
• Example, a man had a terminal B-cell lymphoma (B cell lymphoma)
that had metastasized to the liver, spleen, bone marrow, and
peripheral blood. (all have a same antigenic specificity).
• Mouse mAb specifi c for the B-lymphoma idiotype, injected into the
patient, it bound specifically to only the B-lymphoma cells that
expressed that particular idiotype immunoglobulin. Since B-
lymphoma cells are susceptible to complement-mediated lysis, the
mAb activated the complement system and lysed the lymphoma
cells without harming other cells.
Monoclonal Antibodies can be targeted to tumor cells
• Custom approach targeting idiotypes like this is very costly and
requires a specific reagent for each lymphoma patient. A more
general mAb therapy for B-cell lymphoma is based on the fact
that most B cells, whether normal or cancerous, bear lineage-
distinctive antigens. For example, mAbs that target the B-cell
marker CD20, such as Rituximab, are widely used to treat non-
Hodgkin’s lymphoma.

• Some of the mAbs in clinical use can be coupled with radioactive

isotopes, chemotherapy drugs, or potent toxins of biological
origin. In such “guided missile” therapies,
Development of a monoclonal antibody specific for idiotypic determinants on B-lymphoma
cells. Because all the B-lymphoma cells in a patient are derived from a single transformed B
cell, they all express the same membrane bound antibody (Ab-1) with the same idiotype
(i.e., the same antigenic specificity). In the procedure illustrated, a monoclonal anti-idiotypic
antibody (Ab-2) against the B-lymphoma membrane-bound antibody is produced ex vivo
(steps 1–4). This anti-idiotype antibody is then injected into the patient (step 5), where it
binds selectively to the idiotypic determinants on the immunoglobulin of B-lymphoma cells,
making these cells susceptible to complement mediated lysis.
Monoclonal Antibodies can be targeted to tumor cells
• A variety of tumors express significantly increased levels of
growth factors or their receptors, which are promising targets for
anti-tumor mAbs. For example, in 25% to 30% of women with
metastatic breast cancer, a genetic alteration of the tumor cells
results in the increased expression of human epidermal-growth-
factor–like receptor 2 (HER2) encoded by the neu gene and
expressed in only trace amounts in normal adults.

• Humanized mAb against HER2 has been successfully used to

treat HER2-expressing breast cancers, selectively eliminating
cancer cells without damaging normal cells.
 Cytokines can be used to augment the immune
response to tumor
• Either singly or in combination to augment the immune response
against cancer in clinical trials.

• (IFN-α, β and γ), the tumor necrosis factors (TNF-α and

Lymphotoxin-α (TNF-α), granulocyte-macrophage colony stimulating
factor (GM-CSF) and several interleukins (IL-2,-4, -6, and -12).

• IL-2 alone or in combination with IFN- is still used for advanced

kidney cancer and metastatic melanoma.

• The major obstacles to in vivo cytokine therapy are the complexity

of the cytokine network itself and systemic toxicity.
• Cytokines are also difficult to administer locally, and systemic
administration of high levels of a given cytokine can lead to serious
or even life threatening consequences.
 Tumor specific T cell can be expanded and
reintroduced into patients
• Collect tumor specific T cells from cancer patients, expand and
activate them ex vivo, and re-infuse them into patients.

• These cells can come from solid tumors themselves (tumor

infiltrating lymphocytes, or TILs), tumor-draining nodes, or
peripheral blood.

• Example, the TILs from patients with metastatic melanoma were

collected and expanded with IL-2 in vitro to overcome their
anergic state..
 New therapeutic vaccines may enhance the anti-
tumor immune response
• HPV vaccine, which is up to 99% effective at preventing infection
by the strains that most commonly cause cervical cancer, is not
effective once a women is already infected with one of these
strains.

• Sipuleucel-T (Provenge) became the first approved therapeutic

cancer vaccine.
• This vaccine is designed to fight metastatic prostate cancer by
inducing an immune response to a common self prostate tumor
antigen, prostatic acid phosphatase (PAP).
• This is an individual cell-based therapy, where DCs are first
isolated from prostate cancer patients and then stimulated in
vitro using a fusion protein consisting of PAP and GM-CSF.
• These antigen-stimulated and expanded autologous APCs are
then re-infused into the patient,
Mechanism of action of sipuleucel-T, a prostate cancer vaccine. Autologous DCs are isolated from a patient’s blood and
cultured with a fusion protein consisting of the prostate cancer specifi c antigen PAP and the APC-activating cytokine GM-
CSF (PAP/GM-CSF). DCs take up and process these antigens, after which they are reinfused into the patient in order to
stimulate a T-cell response against PAP expressed on tumor cells in the prostate. Abbreviations: APC, antigen-presenting
cell; DCs, dendritic cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; PAP, prostatic acid phosphatase.
Use of GM-CSF-transfected tumor cells for cancer immunotherapy. Transfection of tumor
cells with the gene encoding GM-CSF allows the tumor cells to secrete high levels
of GM-CSF. This cytokine will activate DCs in the vicinity of the tumor, enabling the DCs to
present tumor antigens to both TH cells and cytotoxic T lymphocyte precursors (CTL-Ps).
 Manipulation of costimulatory signal can improve
cancer immunity
• when mouse CTL precursors (CTLPs) are incubated with melanoma
cells in vitro, antigen recognition occurs.
• In the absence of a costimulatory signal,these CTL-Ps do not
proliferate or differentiate into effector CTLs.
• However, when these melanoma cells are transfected with the gene
that encodes CD80 (B7.1), the CTL-Ps differentiate into effector CTLs.

Use of CD80 (B7.1)-transfected tumor

cells for cancer immunotherapy. Tumor
cells transfected with the B7.1 gene
express the costimulatory CD80 molecule,
enabling them to provide both activating
signal (1) and costimulatory signal (2) to
CTL-Ps. As a result of the combined
signals, the CTL-Ps differentiate into
effector CTLs, which can mediate tumor
destruction. In effect, the transfected
tumor cell acts as an APC.
Combination cancer therapies are yielding surprising
results
• Standard chemotherapeutic treatments for cancer are cytotoxic
to rapidly dividing cells which also kill other rapidly dividing cells,
such as leukocytes (especially those in the myeloid lineage),
were not a good combination with immunotherapeutic
treatments, which aim to stimulate leukocytes.

• Recent evidence suggests otherwise, and current theories

postulate that some of the anticancer benefits of cytotoxic
chemotherapeutic agents may in fact be due to their ability to
induce immune activity against antigens released from killed
tumor cells.
 Drug resistance
• Resistance:
– Inherent (non specific resistance)
• Pseudomonas resistance to many antibiotics
– Acquired
• Staphylococcus aureus develop resistance to penicillin , chloramphenicol,
tetracycline
• Biochemical mechanism of resistance:
• Production of drug inactivating enzymes:
– Inactivation of Aminoglycosides
– β-lactamase (chromosomally or plasmid mediated)
• Extracellular
• Constitutive or inducible
• Gram negative
• Chromosomally mediated hydrolysis cephalosporines, inhibited by cloxacillin (G-ve)
• Aeromonas and klebsiella active against penicillin
• Plasmid mediated (TEM type, Temonieria)
• OXA (oxacillin hydrolysing β-lactamase
 Drug resistance
• Resistance:
– Inactivation of chloramphenicol
• By chloramphenicol acetyl transferease (CAT) plasmid mediated
• Acetylation of OH group
– Changes in the antibiotic target site:
• Alteration of active site
– Chloramphenicol
– Erythromycin
– Penicillin
– Sulphonamides and trimethoprine
– Reduction in cellular permeability
• Polymyxins
• Tetracyclines
• Aminoglycosides
– Switch to alternative metabolic pathways
• Sulfonamides
– Increase production of essential metabolite
• Sulfonamides ----high level of PABA synthesis
 Drug resistance
• Origin of resistance:
– Non-genetic
• Inactive cells
– T.B persistence for years
• Loss of target sites
– Penicillin------L-form cells (no cell wall)
– Genetic
• Chromosomal
– Gene mutation
– Drug combination
• Extra chromosomal
– Plasmid (R-factor)----β-lactamase, CAT
– Transposable elements (jumping genes)
 Drug resistance
• Mechanism of transmission of genetic elements:
– Transduction
– Transformation
– Conjugation
• One or more genes on plasmid
• Resistance transfer factor (RTF),
enable conjugation between resistance
and sensitive bacteria (R-factor)
• Sex pili
• R+ and R-
• Importance:
– Resistance to unrelated drugs
– Transfer occur to unrelated species
– Ex E.coli
– Multi-drug resistant bacteria from farm to man
– Transposition
 Drug resistance
• Specific and resistance:
– Specific
• Resistance to certain drug
– Cross resistance
• If resistance to certain drug may be also resistance to another drug with similar
mech.
• Polymyxin B and polymyxin E
• Erythromycin and oleandomycin
• Neomycin and kanamycin
• Resistance to tertracyclline ---resistance to other group member
 Antibiotic policies
• Unnecessary use of antibiotics in absence of clear indication
– Drug resistance
– Cost
– Toxicity
• When antibiotic should be used:
– Valid reasons to use antibiotics:
• Know infection (clinical or bacteriological tests)
• Prevention of bacterial infection (prophylactic agents)
• Peri-operative prophylaxis
• Risk of life threatening diseases (gas gangarene, penicillin)
– Immediate drug treatment
– Do not use broad spectrum antibiotic when infection can treated with specific
one
– Bactericidal than bacteriostatic, in immunological impaired patients
– Drug combination is recommended in case of T.B (serious)
– Topical infection use antibiotics that do not use systemically (polymyxin)
– Given, long enough, then stop treatment (3 days, 5-7 days)
– Avoid use antibiotic as food supplement (resistance)
– In hospitals or specific area (rotation of antibiotics)
 Drug combination
• Reasons:
– Broad coverage
– Blind therapy
– Synergism (endocarditis, penicillin and aminoglycoside)
– Resistance (T.B)
• inappropriate use will result:
– Antagonism (bactericidal +bacterostatic) less effect than one drug alone
• Penicillin +tetracycline
– Increase number of adverse effects
– Increased cost
..… Thank you